Alkynylnicotinamide‐Based Compounds as ABL1 Inhibitors with Potent Activities against Drug‐Resistant CML Harboring ABL1(T315I) Mutant Kinase

Abstract

The introduction of imatinib into the clinical scene revolutionized the treatment of chronic myelogenous leukemia (CML). The overall eight-year survival rate for CML has increased from about 6 % in the 1970s to over 90 % in the imatinib era. However, about 20 % of CML patients harbor primary or acquired resistance to tyrosine kinase inhibitors. ABL1 point mutations in the BCR-ABL1 fusion protein, such as ABL1(T315I), typically emerge after prolonged kinase inhibitor treatment. Ponatinib (AP24534) is currently the only approved CML drug that is active against the ABL1(T315I) mutation. However, ponatinib has severe cardiovascular toxicities; hence, there have been efforts to find safer CML drugs that work against ABL1 secondary mutations. We reveal that isoquinoline- or naphthyridine-based compounds, such as HSN431, HSN576, HSN459, and HSN608 potently inhibit the enzymatic activities of ABL1, ABL1(T315I), and ABL1(E255K). These compounds inhibit the proliferation of ABL1-driven CML cell lines, K652 and KCL22 as well as the drug-resistant cell line, KCL22-IR, which harbors the secondary mutated ABL1(T315I) kinase.

ANP32B-mediated repression of p53 contributes to maintenance of normal and CML stem cells

“…In addition, Anp32b deletion substantially prolonged the survival of CML mice driven by BCR-ABL1 T315I (supplemental Figure 4I), a CML model resistant to TKIs. 32 Together, these results demonstrate that ANP32B exerts a role in CML development.…”

Continuous Flow Synthesis of Anticancer Drugs

“…Tamoxifen ( 12) is one of the most widely prescribed estrogen receptor modulators used to treat breast cancer, however, it also finds use in the treatment of infertility, gynecomastia, and other disorders [43,[63][64][65]. The typical daily dose is 10 mg, with a treatment lasting over 5 years.…”

“…The reported batch synthesis has several drawbacks such as high catalyst loadings, low yields, long reaction times, and the use of a potentially explosive coupling reagent (HATU) which would be a concern in a large-scale batch synthesis [64,65].…”

Transition‐Metal‐Free Synthesis of 4‐Alkynylquinazolines

“…[3] Compound III has been reported to be a potential colorimetric pH sensor and a chromophore exhibiting a large Stokes shift. [4] Compound IV serves as a tyrosine kinase ABL1 inhibitor [5] (Figure 1). In addition, 4-alkynylquinazoline derivatives have been used as starting compounds for the synthesis of some quinazoline derivatives, which have been the subject of many medical studies on the treatment of cancers and similar topics.…”